Reviews
A review of hereditary and acquired coagulation disorders
in the aetiology of ischaemic stroke
Lonneke M. L. de Lau1, Frank W. G. Leebeek2, Moniek P. M. de Maat2, Peter J. Koudstaal1,
and Diederik W. J. Dippel1
The diagnostic workup in patients with ischaemic stroke
often includes testing for prothrombotic conditions. How-
ever, the clinical relevance of coagulation abnormalities in
ischaemic stroke is uncertain. Therefore, we reviewed what is
presently known about the association between inherited
and acquired coagulation disorders and ischaemic stroke,
with a special emphasis on the methodological aspects.
Good-quality data in this field are scarce, and most studies
fall short on epidemiological criteria for causal inference.
While inherited coagulation disorders are recognised risk
factors for venous thrombosis, there is no substantial evi-
dence for an association with arterial ischaemic stroke. Pos-
sible exceptions are the prothrombin G20210A mutation in
adults and protein C deficiency in children. There is proof of
an association between the antiphospholipid syndrome and
ischaemic stroke, but the clinical significance of isolated
mildly elevated antiphospholipid antibody titres is unclear.
Evidence also suggests significant associations of increased
homocysteine and fibrinogen concentrations with ischaemic
stroke, but whether these associations are causal is still
debated. Data on other acquired coagulation abnormalities
are insufficient to allow conclusions regarding causality. For
most coagulation disorders, a causal relation with ischaemic
stroke has not been definitely established. Hence, at present,
there is no valid indication for testing all patients with
ischaemic stroke for these conditions. Large prospective
population-based studies allowing the evaluation of inter-
active and subgroup effects are required to appreciate the
role of coagulation disorders in the pathophysiology of
arterial ischaemic stroke and to guide the management of
individual patients.
Correspondence: Lonneke M.L. de Lau, Department of Neurology,
Erasmus MC University Medical Center, room H-673, PO Box 2040, 3000
CA Rotterdam, The Netherlands.
E-mail: l.delau@erasmusmc.nl
1
Department of Neurology, Erasmus MC University Medical Center,
Rotterdam, The Netherlands
2
Department of Hematology, Erasmus MC University Medical Center,
Rotterdam, The Netherlands
Conflict of interest: None.
DOI: 10.1111/j.1747-4949.2010.00468.x
& 2010 The Authors.
Journal compilation & 2010 World Stroke Organization International Journal of Stroke Vol 5, October 2010, 385394
Key words: coagulation, haemostasis, interaction, risk factors,
stroke, thrombophilia
Introduction
Stroke is an important cause of death and disability in Western
societies (1, 2). In about 40% of all ischaemic strokes, no
definite cause can be identified, despite extensive ancillary
investigations (3). The diagnostic workup in patients with
ischaemic stroke often includes testing for thrombophilic
conditions. However, the clinical significance of inherited or
acquired coagulation abnormalities found in ischaemic stroke
patients is uncertain (46). For many of the coagulation
disorders, a causal relation with arterial ischaemic stroke has
not been definitely established, and it is still argued whether
and how these conditions should be treated to prevent
(recurrent) stroke. In this article, we will review what is
presently known about the association between coagulation
disorders and arterial ischaemic stroke, with a special emphasis
on the methodological quality of the available evidence, and
discuss the usefulness of laboratory testing for prothrombotic
conditions in ischaemic stroke patients.
Methodological considerations
Several points are of importance when assessing the strength of
the evidence in favour of a true causal relation between a
certain coagulation abnormality and ischaemic stroke. Evi-
dently, the supposed association should be biologically plau-
sible. Furthermore, a causal link is more likely when the data
suggest a doseresponse relationship, i.e. an increasing prob-
ability of stroke with increasing severity of the potential risk
factor. In genetic studies, additional proof of causality may
emerge from relating gene variations to the levels or function
of the gene product. Other key issues in interpreting and
weighing results from the literature are the design and the size
of the study. The research in this field largely consists of case
control studies, which are prone to several methodological
pitfalls such as reversed causality and inappropriate selection
of controls. Most of the available data have been obtained in
relatively small studies that are probably underpowered to
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 Reviews L. M. L. de Lau et al.

detect modest effects. Limited statistical power due to low
numbers in individual studies can be partly overcome by meta-
analyses. Still, negative results have a lower probability of
appearing in print than statistically significant associations,
leading to a publication bias. Unfortunately, the majority of the
studies on coagulation disorders and ischaemic stroke are
inadequate with respect to many of the above-mentioned
points, thus hampering causal inference.
Inherited coagulation disorders
Inherited prothrombotic coagulation disorders are caused by
mutations in genes encoding for factors involved in the
coagulation cascade, in particular, anticoagulant proteins
and coagulation factors. Most of these hereditary prothrom-
botic conditions were consistently found to be associated with
an increased risk of venous thrombotic and thromboembolic
events. Yet, for arterial thrombosis including ischaemic stroke,
the findings have been far less consistent and a causal associa-
tion is still disputed.
Protein C deficiency
Protein C is a vitamin-K-dependent protein, which circulates
in the blood in an inactive form. Activated protein C (APC)
inhibits clot formation by proteolytic degradation of activated
coagulation factors V and VIII (7). Inherited deficiency of
protein C, which is estimated to occur in 0205% of the
general population, results in a hypercoagulable state and is
associated with an increased risk of venous thrombotic events
(8). Many different mutations have been identified in the gene
encoding for protein C, resulting in several types of protein C
deficiency. Most patients have a heterozygous protein C
deficiency, with a protein C level of around 50% of normal.
A limited number of studies have investigated protein C levels
or protein C deficiency in relation to ischaemic stroke. A few
case reports and smaller casecontrol studies have suggested an
association between protein C deficiency and ischaemic stroke
(9, 10), but in a larger casecontrol study, no significant
association was observed (5). In the prospective ARIC study,
lower levels of protein C seemed to be related to an increased
risk of incident ischaemic stroke, but the results were not
statistically significant (Table 1) (11). It is noteworthy that only
single measurements of protein C antigen concentration were
analysed and that the levels were truly deficient in just a few
participants in this cohort. In the same study, baseline protein
C was also associated with cerebral infarcts on MRI at follow-
up, although baseline MRIs were not available (12). Most other
studies on protein C deficiency and ischaemic stroke involve
paediatric patients. A prospective study among 301 children
with a first ischaemic stroke showed a significantly increased
risk of recurrent ischaemic stroke in children with hereditary

Table 1 Published meta-analyses and prospective studies (cohort studies or nested casecontrol studies) on the relation between hereditary coagulation
disorders and ischaemic stroke

Population Coagulation factor Author (reference) Year Outcome Studiesw Cases Controls (Pooled) OR (95% CI)

Children Protein C Haywood et al. (14) 2005 F 11 470 1081 649 (2961427)
Strater et al. (13) 2002 R NAz 20 301 350 (11109)
Protein S Haywood et al. (14) 2005 F 9 428 944 114 (034380)
Strater et al. (13) 2002 R NAz 20 301 29 (08113)
Antithrombin Haywood et al. (14) 2005 F 8 435 952 102 (028367)
FV Leiden Juul et al. (20) 2002 F 7 369 1100 479 (326703)y
Haywood et al. (14) 2005 F 9 629 2004 122 (080187)
PT G20210 Haywood et al. (14) 2005 F 7 550 1902 11 (051234)
Adults Protein C Folsom et al. (11) 1999 F NAz 191 14522 099 (0912)z
Protein S No meta-analyses or
prospective studies
Antithrombin Folsom et al. (11) 1999 F NAz 191 14522 107 (0912)z
FV Leiden Juul et al. (20) 2002 F 9 1422 9441 100 (075134)
Casas et al. (21) 2004 F 26 4588 13798 133 (112158)J
Kim and Becker (19) 2003 F 15 3039 12200 127 (086187)
Cushman et al. (23) 1998 F NAz 149 482 077 (03517)
Ridker et al. (22) 1995 F NAz 209 704 10 (0422)
Juul et al. (20) 2002 F NAz 410 8835 068 (045104)
PT G20210 Kim and Becker (19) 2003 F 10 1625 5050 13 (091187)
Casas et al. (21) 2004 F 19 3028 7131 144 (111186)
Ridker et al. (26) 1999 F NAz 259 1774 11 (0524)
Smiles et al. (27) 2002 F NAz 182 453 140 (051386)
Outcome; F, first-ever stroke; R, recurrent stroke. wNumber of studies included in meta-analysis. zProspective study. yAll studies also included in meta-
analysis of Haywood and colleagues, except for one study performed among neonates, showing a significant association between the FVL mutation and
ischaemic stroke (OR 395, 95% CI 17290). zOR per SD increase. JSignificant interstudy heterogeneity, OR after exclusion of responsible study 118
(098142). CI, confidence interval; OR, odds ratio. Bold indicates statistically significant associations.

& 2010 The Authors.

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 L. M. L. de Lau et al.
protein C deficiency (13). A meta-analysis of 11 casecontrol
studies also reported a significant association between protein
C deficiency and first arterial ischaemic stroke in children (14).
Protein S deficiency
Protein S, another vitamin-K-dependent protein, is a co-factor
in the process of the proteolytic inactivation of factor Va and
VIIIa by APC, and thus exerts an inhibiting effect in the
coagulation cascade (8). Several mutations have been de-
scribed that cause hereditary protein S deficiency. A few cases
with homozygous or compound heterozygous protein S
deficiency have been reported, displaying a severe form of
thrombosis at a young age. Heterozygous protein S deficiency
is more frequent and has been linked to an elevated risk of
venous thromboembolic events in many studies (8, 15).
The relationship between protein S deficiency and the risk of
ischaemic stroke in adults has hardly been investigated system-
atically (Table 1). Published reports include small studies, case
reports or patient series without controls (8, 16, 17). Prospec-
tive studies have not been performed. One relatively large case
control study did not demonstrate a significant association
between protein S deficiency and the risk of ischaemic stroke
(5). In their meta-analysis of nine casecontrol studies, Hay-
wood et al. (14) did not find a significant association in
children either.
Antithrombin deficiency
Antithrombin is a serine protease inhibitor that inactivates
thrombin, as well as other coagulation enzymes, including
activated factors X, IX, XI and XII (8). It thus functions as a
natural anticoagulant. Several mutations in the antithrombin
gene have been identified that can cause antithrombin defi-
ciency. The inheritance pattern is usually autosomal domi-
nant. The deficiency of antithrombin results in a
hypercoagulable state and is associated with an increased risk
of venous thromboembolism (8). As yet, no substantial
evidence has been obtained for an association between antith-
rombin deficiency and the risk of arterial ischaemic events,
including stroke (Table 1). A large casecontrol study (5) and
one prospective study (11) both failed to demonstrate an
association with ischaemic stroke of hereditary antithrombin
deficiency and antithrombin levels, respectively. Studies per-
formed in paediatric patients were also negative; a meta-
analysis of eight casecontrol studies did not show an associa-
tion between antithrombin deficiency and the risk of incident
ischaemic stroke in children (14).
Factor V Leiden (FVL) mutation
The FVL mutation is a common mutation (1691 G4A) in the
gene coding for coagulation factor V, resulting in factor Va
being resistant to degradation by APC (18). Activated protein
C resistance, either due to the FVL mutation or caused by other
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Reviews
genetic or acquired factors, is the most frequently known
independent risk factor for venous thrombosis. The risk of
venous thrombosis is estimated to be increased by a factor 57
in heterozygous carriers and a factor 50100 in homozygous
carriers (7). It is debated whether the FVL mutation is also
associated with the occurrence of arterial thrombosis. No
significant association between the FVL mutation and the
risk of ischaemic stroke in adults was found in two meta-
analyses of nine and 15 casecontrol studies, respectively
(Table 1) (19, 20). A third meta-analysis including 26 case
control studies on the FVL mutation demonstrated an associa-
tion with ischaemic stroke, but the result was no longer
statistically significant after one study was excluded, which
caused a significant interstudy heterogeneity (21). In a nested
casecontrol study within the prospective Physicians Health
Study as well as in the large prospective Cardiovascular Health
Study, there was no association between the FVL mutation and
the occurrence of stroke (22, 23). Some, but not all studies
performed in children suggest that the FVL mutation might be
a risk factor for ischaemic stroke in this subgroup (14, 24).
Prothrombin G20210A mutation
The G20210A mutation in the 30 untranslated region of the
prothrombin gene results in elevated plasma levels of pro-
thrombin (factor II), the precursor of thrombin. Persons
carrying this mutation, in particular homozygous individuals,
were found to have an up to threefold increased risk of venous
thrombosis (25). The relation between the prothrombin
G20210A mutation and the risk of ischaemic stroke has been
evaluated prospectively in two large population studies. In the
Physicians Health Study as well as the Cardiovascular Health
Study, no significant association was observed between the
presence of the prothrombin mutation and the occurrence of
ischaemic stroke (Table 1) (26, 27). Of the retrospective case
control studies that have been published, a significant associa-
tion was seen in only two, whereas the majority did not
demonstrate a relationship (4). However, while in a meta-
analysis of 10 studies, the summary estimate was not statisti-
cally significant (19), a larger meta-analysis of 19 casecontrol
studies showed a modest but statistically significant associa-
tion (21).
Protein Z
Protein Z is a vitamin-K-dependent glycoprotein that func-
tions as a cofactor in the inhibition of activated coagulation
factor X by a protein Z-dependent protease inhibitor (28).
Pathophysiological studies suggest that protein Z may exert
anticoagulant as well as procoagulant effects (29, 30). The
results of several casecontrol studies did not support the
theory of a link between protein Z levels and venous throm-
bosis (28). A number of casecontrol studies examined the
association between protein Z levels and arterial stroke, with
quite contradictory findings. In some studies, low plasma
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levels of protein Z were associated with an increased risk of
ischaemic stroke (30, 31), while other groups found an
increased risk of stroke with elevated protein Z levels
(3234), or no relation at all (35). In the large prospective
ARIC study, there was no statistically significant association
between protein Z levels and stroke (36). Two polymorphisms
(G79A and G103A) of the gene encoding for protein Z have
been evaluated in relation to the occurrence of arterial stroke in
a few casecontrol studies, but the results were not consistent
(30, 34, 37).
Acquired coagulation disorders
A number of acquired conditions are also associated with a
hypercoagulable state. Some of these disorders seem to be
linked to an increased risk of both venous and arterial
thrombosis, although the evidence for a causal relation is
uncertain.
Antiphospholipid antibodies
Antiphospholipid antibodies are acquired autoantibodies di-
rected against phospholipids or phospholipidprotein com-
plexes (38). The antiphospholipid syndrome (APS) is a
systemic autoimmune disorder characterised by elevated levels
of antiphospholipid antibodies in combination with at least
one clinical episode of arterial, venous or small-vessel throm-
bosis in any tissue or organ, or pregnancy morbidity (un-
explained foetal death, premature birth due to (pre)-eclampsia
or placental insufficiency or repeated unexplained sponta-
neous abortions). According to the updated international
consensus criteria, laboratory findings should be present on
two or more occasions at least 12-weeks apart (39). The
prothrombotic state in APS that is associated with an increased
risk of recurrent venous and arterial thromboembolic events is
still debated, but is thought to be mainly caused by the
activation of endothelial cells and platelets by antiphospholi-
pid antibodies (38). Moderately and often transiently elevated
titres of antiphospholipid antibodies can also be found in
patients with infections or certain medication. The clinical
significance of antiphospholipid antibodies in the absence of
other criteria for APS is unclear. Furthermore, studies are
hampered by the considerable degree of heterogeneity of
available laboratory tests to detect antiphospholipid antibo-
dies and the ongoing debate on the serological criteria of APS
(40, 41). Although in many casecontrol studies a relation
between antiphospholipid antibodies and an increased risk of
ischaemic stroke was found (4244), others did not demon-
strate such an association (45, 46). Prospective studies have
yielded inconsistent results as well (4750). In the largest
prospective study, elevated titres of anticardiolipin antibodies
were significantly associated with future ischaemic stroke, but
only in women (50). A prospective study on recurrent stroke
found no association between the presence of antiphospholi-
pid antibodies at the time of the initial stroke and the risk of
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L. M. L. de Lau et al.
subsequent thrombo-occlusive events (49). Several studies
have suggested that the presence of antiphospholipid anti-
bodies is associated with ischaemic stroke specifically in the
subgroup of young adults (51).
Coagulation disorders associated with cancer
Several publications have suggested that stroke occurs more
frequently in patients with malignant disease as compared with
the general population (5254), although others could not
replicate this observation (55). A variety of mechanisms might
underlie the potentially higher incidence of stroke in cancer
patients, including direct tumour effects (tumour embolism,
vessel compression), therapy-related factors (surgery, radio-
therapy-induced vasculopathy, hormonal therapy) and coa-
gulation disorders. Malignant disease may induce a low-grade
systemic activation of coagulation, which is related to an
increased risk of venous thromboembolic events (56, 57).
Findings from several studies also suggest an association
between cancer-related coagulation disorders and arterial
ischaemic stroke. In an autopsy study of 3426 patients who
died of systemic cancer, evidence of a hypercoagulable state was
found in over half of the patients with symptomatic stroke
(53). A smaller retrospective casecontrol study comparing
ischaemic stroke patients with and without cancer showed a
trend towards more thrombotic events in patients with
malignant disease (58). In another retrospective study, coagu-
lation abnormalities were present in a considerable proportion
of patients in whom ischaemic stroke was the first manifesta-
tion of an underlying malignancy (59). However, without any
results from large prospective series, there is no definite proof
of an elevated risk of arterial ischaemic stroke related to
coagulation abnormalities in malignancies.
Hyperhomocysteinaemia
Homocysteine is a nonessential amino acid that is metabolised
by two major pathways: remethylation to methionine, requir-
ing folate and vitamin B12, and transsulphuration to cy-
stathionine, with vitamin B6 as a cofactor. In the 1960s,
several patients were reported with extremely high plasma
levels of homocysteine who developed venous and arterial
thrombosis at very young ages. These children displayed
evidence of premature atherosclerosis as well as characteristics
of a hypercoagulable state. The strongly increased levels of
homocysteine (4100 mmol/l) were later found to be caused by
a number of rare inborn errors of homocysteine metabolism
(60, 61). As opposed to these uncommon genetically deter-
mined forms of hyperhomocysteinaemia, a mildly elevated
homocysteine concentration (415 mmol/l) is more frequent
and is often due to the dietary deficiency of B-vitamins, older
age or renal failure (62). Evidence from the last two decades
suggests that mild hyperhomocysteinaemia is also associated
with an increased risk of venous and arterial thrombotic
disease. Numerous epidemiological studies have shown a
& 2010 The Authors.
 L. M. L. de Lau et al.
positive association between homocysteine concentration and
the risk of cardiovascular disease, including stroke. A meta-
analysis of 12 prospective and 18 retrospective studies showed
that a 25% lower total homocysteine concentration was
associated with a significantly lower risk of stroke, after
adjustment for cardiovascular risk factors (63). Another
meta-analysis, based on eight prospective studies, also demon-
strated a statistically significant relation between elevated
homocysteine levels and the risk of stroke. Furthermore, the
same authors reported an increased risk of stroke associated
with the MTHFR 677TT genotype, which causes a mild
hyperhomocysteinaemia (64). Supplementation with folate,
vitamin B12 and vitamin B6 has been shown to reduce
homocysteine concentrations (65). Yet, several large rando-
mised trials have failed to demonstrate an effect of vitamin
supplementation on the risk of cardiovascular disease or
atherosclerosis, despite successful lowering of homocysteine
(6669). Disappointing trial results initially raised the ques-
tion as to whether hyperhomocysteinaemia is truly causally
related to cardiovascular risk or rather an epiphenomenon or a
marker of other pathological processes such as deficiencies of
B-vitamins (65, 70) However, recent evidence indicates that
there might be an effect of supplementation specifically on the
risk of stroke. The results of the large HOPE-2 trial were
negative for the primary composite study endpoint, but for
stroke, a 24% risk reduction associated with vitamin supple-
mentation was found (66). This fits the results from two meta-
analyses of trials on vitamin supplementation, showing in-
sufficient evidence for an effect on cardiovascular disease, but a
borderline significant effect on stroke risk (71, 72). Laboratory
studies indicate that homocysteine has both atherogenic and
thrombogenic properties (65), but the exact biological me-
chanisms that underlie the relation between elevated homo-
cysteine concentration and ischaemic stroke are not well
understood.
Disturbances of primary haemostasis
Von Willebrand factor (vWF) is a glycoprotein that plays an
important role in primary haemostasis by stimulating platelet
adhesion and aggregation. It has been suggested that high vWF
levels may have a pathogenetic role in cardiovascular disease
(73). In one casecontrol study, high levels of vWF antigen and
activity were indeed associated with an increased risk of first-
ever ischaemic stroke (74). The large vWF multimers are
cleaved into smaller, less active forms by the metalloprotease
ADAMTS13 (A Disintegrin And Metalloprotease with Throm-
boSpondinmotifs). A recent casecontrol study showed that
lower plasma levels of ADAMTS13 were related to an increased
risk of cardiovascular disease in young individuals (75).
A complete deficiency of ADAMTS13 is seen in thrombotic
thrombocytopaenic purpura (TTP), a thrombotic microan-
giopathy characterised by occlusive microvascular thrombosis,
microangiopathic haemolytic anaemia, consumptive throm-
bocytopaenia and organ dysfunction. Insufficient processing
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of vWF multimers results in continuing vWF-dependent
intravascular platelet aggregation, eventually causing micro-
vascular thrombosis. Diffuse neurological symptoms such as
behavioural changes, disturbed consciousness or convulsions
are commonly seen in TTP, due to the occlusion of small vessels
in the brain. These symptoms and associated radiological
findings are usually transient (76). In a study of 48 patients
diagnosed with TTP or haemolytic uraemic syndrome
(HUS; another thrombotic microangiopathy), neurological
abnormalities were found in 73% (77), a proportion similar to
that in another small study of 16 TTP patients (76). Ischaemic
stroke does not seem to be the main complication of throm-
botic microangiopathies, as neurological complications were
mostly suggestive of microvascular occlusive changes and focal
deficits were only seen in a minority of these patients.
A number of case reports have been published of ischaemic
stroke or persisting focal lesions on MRI occurring in TTP or
HUS (7880), but systematic studies including a control group
have not been carried out.
Several polymorphisms of genes encoding for platelet
receptors have been evaluated in relation to ischaemic stroke
occurrence, including the PlA1/A2 polymorphism of the
platelet glycoprotein IIb/IIIa receptor, and variations in the
purinergic receptor P2Y G-protein-coupled 12 (P2RY12) gene,
but thus far, no evidence has been observed for an association
with ischaemic stroke (8183).
Disorders of fibrin formation and fibrinolysis
Fibrinogen, the central protein in the coagulation cascade, is a
soluble acute-phase protein that is converted into insoluble
fibrin by thrombin. Fibrin is then cross-linked by coagulation
factor XIIIa to form blood clots. High fibrinogen levels have
consistently been associated with an increased risk of ischae-
mic stroke in prospective studies. A large meta-analysis of data
from 31 population-based prospective studies confirmed the
significant association between plasma fibrinogen and arterial
ischaemic stroke (84). However, it is still unclear whether
raised plasma fibrinogen contributes directly to the occurrence
of ischaemic stroke or rather reflects general inflammation or
severity of atherosclerosis, resulting in an increase of inflam-
matory markers (44, 85). To further evaluate the nature of the
association, studies of genetic variations as markers for fibri-
nogen levels have been performed, some of which indeed
suggested a relation between various polymorphisms or hap-
lotypes and the occurrence of ischaemic stroke (44, 86).
The levels or the activity of coagulation factor XIII report-
edly are influenced by genetic variation, but studies on the
relation between several variants of the genes encoding for the
A and B subunits of factor XIII and ischaemic stroke have been
inconsistent (8789).
Impaired fibrinolysis has also been suggested to be
associated with arterial thrombosis, including ischaemic
stroke (90). In a recent casecontrol study, increased clot lysis
times, indicative of hypofibrinolysis, were found in patients
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with arterial thrombotic disease at a young age, with a trend
towards elevated clot lysis times in the subgroup of patients
with ischaemic stroke (91). Several casecontrol studies have
demonstrated an association between plasma levels of throm-
bin-activatable fibrinolysis inhibitor (TAFI) and ischaemic
stroke (9294). One of these also revealed an association
between the 325Thr/Ile polymorphism of the TAFI gene and
arterial thrombosis. A recent meta-analysis including about
2500 cases and 3500 controls demonstrated strong evidence of
an association with ischaemic stroke of the 4G/5G promoter
polymorphism of the gene encoding for another inhibitor of
fibrinolysis, plasminogen activator inhibitor-1 (PAI-1), with a
large heterogeneity across studies (95). Unfortunately, almost
all studies reported on genotype only, instead of genotype and
levels simultaneously. In one casecontrol study evaluating
both the 4G/5G polymorphism and the PAI-1 antigen levels,
no association was found between PAI-1 levels and first
ischaemic stroke (96).
Interactive effects
Arterial thrombosis including ischaemic stroke is increasingly
considered a multifactorial disease, similar to venous throm-
bosis, which is thought to result from an interaction between
genetic and nongenetic (environmental or behavioural) risk
factors (1, 7, 25). Most individuals with a single coagulation
disorder do not develop thrombosis, and in many cases of
venous thrombosis, more than one predisposing factor is
involved, e.g. an inherited thrombophilia in combination
with another risk factor such as pregnancy, surgery, trauma
or immobilisation. For many of the coagulation disorders, the
effect on arterial ischaemic stroke, if any, is only
modest. However, some studies indicate that coagulation
disorders that individually have no or limited influence are
associated with an increased risk of stroke in coexistence with
another risk factor.
Patent foramen ovale
Patent foramen ovale (PFO), a persisting opening in the
septum between the left and the right atrium of the heart, is
estimated to be present in over 25% of the general population
(97). Several casecontrol studies and one meta-analysis found
a higher frequency of PFO in patients with cryptogenic stroke
as compared with the control group, in particular, in the
younger age groups (9799). In a prospective study among 581
ischaemic stroke patients aged 1855-years, the presence of
both PFO and atrial septal aneurysm, but not PFO alone, was
significantly associated with an elevated risk of recurrent stroke
(100). However, it is still disputed whether PFO and ischaemic
stroke are causally related, and if so, what might be the
underlying mechanism. A number of theories have been
proposed, the idea of a paradoxical embolism from the
peripheral venous system through the PFO to the brain being
the oldest and best known. Yet, deep venous thrombosis, either
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L. M. L. de Lau et al.
with or without accompanying Valsalva manoeuvre, is very
rare in patients with PFO who suffer ischaemic stroke. Alter-
natively, it has also been suggested that the PFO tunnel itself
might be a source of thrombi or that the PFO might induce
thrombus formation due to transient arrhythmias (97, 101).
The presence of a hypercoagulable state is assumed to increase
the risk of ischaemic stroke in patients with PFO by promoting
the formation of venous thromboemboli or enhancing the risk
of direct embolisation from the PFO. A number of case
control studies indeed suggest that the presence of the pro-
thrombin G20210A or the FVL mutation is associated with an
increased risk of ischaemic stroke in patients with PFO (101
104). Prospective studies investigating the interaction between
PFO and coagulation abnormalities in relation to ischaemic
stroke have not been published thus far.
Oral contraceptive use
There is still disagreement whether the use of oral contra-
ceptives should be considered an independent risk factor for
ischaemic stroke, as results from studies evaluating this
relationship have been contradictory. However, in a large
meta-analysis of 16 casecontrol studies, current contraceptive
use was significantly associated with the occurrence of ischae-
mic stroke, with evidence of a doseresponse relationship
(105). A limited number of studies have examined the inter-
action between coagulation disorders and oral contraceptive
use. A small casecontrol study showed that the risk of
cryptogenic ischaemic stroke was most marked in women
who used oral contraceptives and had either the FVL or the
prothrombin G20210A mutation (106). In other casecontrol
studies, an increased risk of stroke was observed in women
using oral contraceptives who also carried the FVL mutation,
the MTHFR 677TT genotype or had hyperhomocysteinaemia
(107109). A definite pathophysiological explanation for these
synergistic effects is lacking, but it has been found that the use
of oral contraceptives causes acquired resistance to activated
protein C and decreased concentrations of free and total
protein S, although the biological basis of this finding is
unknown (110).
Atherosclerotic lesions
There is evidence that the presence of atherosclerotic lesions, in
particular, vulnerable plaques prone to rupturing, is related to
platelet activation, initiation of the coagulation cascade and an
increased fibrin turnover (111). Therefore, it has been hy-
pothesised that the presence or the severity of atherosclerosis
might affect the risk of thrombotic events in the venous system.
Proof for this hypothesis comes from a casecontrol study
showing that asymptomatic carotid artery atherosclerosis as
measured by ultrasonography was more frequent in patients
with a deep venous thrombosis of unknown origin than in
those with secondary thrombosis and in control subjects
(112). However, in two prospective population-based cohort
& 2010 The Authors.
 L. M. L. de Lau et al.
studies, no association was found between measures of sub-
clinical atherosclerosis (carotid intimamedia thickness or the
presence of atherosclerotic plaques) and the occurrence of
venous thromboembolic events during follow-up (113, 114).
It is conceivable that the simultaneous existence of athero-
sclerotic lesions, especially disrupted plaques, and a coagula-
tion disorder might exert a synergistic effect on the risk of
arterial ischaemic stroke. Although this interaction has not
been evaluated systematically thus far, it offers an interesting
basis for future research now that noninvasive techniques such
as multislice CTand MRI have become available to evaluate the
burden of carotid atherosclerotic disease (115).
Discussion
There is a lack of methodologically sound studies on the
relation between coagulation disorders and arterial ischaemic
stroke. Most of the published research falls short on the criteria
for causality that we mentioned in the introduction, and
publication bias has almost certainly influenced the literature.
Nearly all studies had a retrospective casecontrol design,
which is susceptible to different sorts of bias. Poor selection
of controls may lead to biased findings and incorrect conclu-
sions, in particular, in studies concerning specific subgroups
such as children or young adults. In addition, reversed
causality may have played a role when measurements were
carried out after stroke onset, for example of factors that are
influenced by inflammation such as fibrinogen or PAI-1.
Coagulation abnormalities could be secondary to the occur-
rence of ischaemic stroke, or due to an acute-phase reaction,
and the results of retrospective studies should therefore be
interpreted with caution. Limited sample size often results in
insufficient statistical power. Especially studies on genetically
determined disorders are likely underpowered, as the effects of
single genetic variations are expected to be small. This is
illustrated by the fact that for some of the inherited coagulation
disorders, most individual studies failed to demonstrate a
relation to ischaemic stroke, whereas meta-analyses suggest a
modest, yet significant association. Large prospective studies
are scarce, and some of them also have limitations. In many
instances, measurements of protein C, protein S or antith-
rombin were performed just once, while acquired and transient
decreases in the levels of these proteins are far more frequent
than hereditary deficiencies (4). Antiphospholipid antibodies
may also be transiently elevated due to non-specific causes, but
repeated laboratory testing was not performed in most studies
either. Furthermore, only a few studies allowed for the evalua-
tion of potential doseresponse relationships, and many
genetic studies failed to explore the relation between genetic
variations and the levels or the function of the gene product.
Finally, only a few studies have simultaneously evaluated
multiple coagulation abnormalities or potential risk factors
for thrombosis, thus allowing the possibility to study interac-
tions between several genetic and nongenetic factors. Moder-
ate effects of coagulation disorders that only occur in the
& 2010 The Authors.
Journal compilation & 2010 World Stroke Organization International Journal of Stroke Vol 5, October 2010, 385394
Reviews
presence of another factor might thus be missed. From this
point of view, a casecrossover approach, when technically
feasible, could be a promising approach.
Given the methodological shortcomings in the available
literature, there is clearly a need for large, prospective popula-
tion-based studies evaluating the role of coagulation abnorm-
alities in the pathophysiology of arterial ischaemic stroke.
In order to allow conclusions regarding causality and to guide
the management of individual patients, prospective data are
required especially on the hereditary coagulation disorders, the
presence of antiphospholipid antibodies without APS and as
yet scarcely investigated factors such as vWF, ADAMTS13 and
PAI-1. Large intervention studies should solve the issue of
whether or not homocysteine lowering might prevent (recur-
rent) stroke (86), and larger studies are needed to appreciate
the role of genetic variations.
There is currently no consensus about the value of screening
for coagulation disorders in patients with arterial ischaemic
stroke (46). Most authors do not recommend routine testing
for inherited coagulation disorders, but some state that it
might be valuable in younger patients (4, 8, 116). At present,
convincing evidence for a relationship with ischaemic stroke of
hereditary deficiencies of protein C, protein S, and antithrom-
bin, the FVL and prothrombin G20210A mutations and
protein Z levels is lacking, possibly with the exception of the
prothrombin G20210A mutation in adults and protein C
deficiency in children. Hence, there is no valid indication for
testing all patients with arterial ischaemic stroke for these
conditions. The APS is almost by definition associated with an
increased risk of ischaemic stroke. Still, data on mildly elevated
titres of antiphospholipid antibodies without other features of
APS are conflicting. According to some, testing should be
conducted in every stroke patient (4), or only in young persons
or patients with other features of APS (51), whereas others feel
that given the current evidence, it is not appropriate at all (49).
The lack of therapeutic implications should topple the balance.
Current evidence does not justify diagnostic testing for malig-
nant disease in patients who experienced arterial ischaemic
stroke. In spite of the evidence for a significant but modest
association between increased homocysteine and ischaemic
stroke, routine assessment of homocysteine levels after an
ischaemic stroke should not be recommended either, as
causality of this association is still debated and definite proof
for the effect of treatment with vitamin supplementation is
lacking (60). Including fibrinogen measurements in the diag-
nostic workup of stroke patients would also be premature at
this time, given the uncertainty about clinical significance, the
proper timing of fibrinogen measurements and appropriate
cut-off points (117). Finally, the existing data do not support
assessments of vWF, ADAMTS13, TAFI, PAI-1 or genetic
variations of factors involved in coagulation. Nevertheless,
each individual stroke patient merits a tailor-made diagnostic
workup, sometimes including tests for certain coagulation
disorders. On the other hand, it should be emphasised that a
diagnosis of a coagulation disorder in a patient who suffered an
391
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ischaemic stroke does not obviate the necessity of a full
diagnostic workup.
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